Sexual Dysfunctions in Females with Parkinson’s Disease: A Cross-Sectional Study with a Psycho-Endocrinological Perspective

Background and Objectives: Normal human sexual functioning is a complex integration of an intact neuroanatomic substrate, vascular supply, a balanced hormonal profile, and a predominance of excitatory over inhibitory psychological mechanisms. However, sexual functioning in Parkinson’s disease (PD) is often overlooked in clinical practice, especially in female patients. Materials and Methods: In this cross-sectional study, we have investigated the frequency of sexual dysfunction and the possible correlation with psycho-endocrinological factors in a sample of women with idiopathic PD. Patients were assessed using a semi-structured sexual interview, in addition to psychometric tools, including the Hamilton Rating Scale for Anxiety and for Depression and the Coping Orientation to the Problems Experiences—New Italian Version. Specific blood tests, including testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen E2, prolactin (PRL), and vitamin D3 were also evaluated. Results: Our results reported a statistical difference in sexual intercourse frequency before and after the onset of PD (p < 0.001). The percentage of women who complained about reduced sexual desire increased after diagnosis (52.7%) compared to the period before the onset of the illness (36.8%). The endocrinological profile in females with PD revealed statistically significant differences regarding testosterone (p < 0.0006), estradiol (p < 0.00), vitamin D3 (p < 0.006), and calcium (0.002). Depression (44% characterized by perceived feelings of anger and frustration during sexual intercourse) and anxiety symptoms (29.5% reported feelings of fear and anxiety for not satisfying the partner) with abnormal coping strategies (48.14% experienced feelings of anger and intolerance) were also found to be statistically significant. This study showed a high frequency of sexual dysfunction in female patients with PD, which correlated with sexual hormone abnormalities, mood/anxiety, and coping strategies alterations. This supports the idea that there is a need to better investigate the sexual function of female patients with PD to provide them with an adequate therapeutic approach and potentially improve quality of life.


Introduction
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, affecting about 3% of the population by the age of 65 and up to 5% of the people over 85 years [1,2]. PD causes a progressive neuronal dopaminergic loss in the substantia nigra compacta and the storage of alpha-synuclein-positive cytoplasmic inclusions termed Lewy bodies [3,4]. The role of biological sex is an important factor in the development of PD. Indeed, sex-based differences have been found for factors that influence the development and phenotypical expression as well as the life prognosis of patients with PD [5,6]. Epidemiological and clinical features highlight the clear presence of sex-related differences, per PD, The local Ethics Committee approved this study (IRCCSME-18/2021) on 15 October 2021. Written informed consent was obtained from all participants, and the principles outlined in the Declaration of Helsinki were followed.

Procedures
The assessment was conducted according to the "on" phase of PD patients, on the same day of the routine neurological consultation by a multiprofessional team composed of a neurologist/sexologist, an endocrinologist, and a psychiatric rehabilitation technician. This latter administered the psychometric evaluation, the endocrinologist prescribed specific hormonal and vitamin dosages to investigate those abnormalities potentially affecting wellbeing and sexual function [47], while the neurologist/sexologist carried out the neurological examination and sexual consultation. The frequency of sexual dysfunctions was investigated via the administration of a specific questionnaire. Social and demographic information, including age, ethnic background, residency (rural or urban), educational level, religion, and marital status, were also collected.

Outcome Measures
The sexual questionnaire (a semi-structured interview created by the research team in the native language of the patients, i.e., Italian, and translated into English only for publication purposes; see Supplementary Materials) is composed of twenty-eight questions focused on specific sexual topic about the woman's sexual life, including sexual desire, arousal, lubrication, orgasm, satisfaction, frequency and quality of sexual intercourse, and intimacy experience [48]. In addition, it investigates some behavioral aspects, such as mood, anxiety during sexual intercourse, and specific opinions/beliefs on the influence of the disease on sexual life and the level of satisfaction. Information about patients' sexuality (i.e., sexual desire, sexual intercourse frequency, etc.) was related to two different periods: before diagnosis and after diagnosis. Notably, Questions 13 and 14 were asked to the partners (when applicable) to better understand relationship problems. Answers were either dichotomic (yes or no) or as open. However, for specific questions, a 5-point Likert scale was used. In particular, the scale was applied to Item 5, investigating the quality of relationship as well as to Items 17-22 assessing the level of satisfaction about the relationship with the partner. Regarding Items 25 and 27 that evaluate SD (pre-and postmorbid sexual desire) in relation to the PD's diagnosis, the patient must assign a score from 1 to 3 (1 = absent/reduced sexual desire; 2 = poor, but present; 3 = preserved). We decided to use this specific interview to collect more information about patients' disease-related sexual life and their satisfaction degree regarding their relationships, which is not present in other validated tools. Although the semi-structured interview has not been validated, it has been used in other neurological conditions as a complementary and valuable tool [31,47,48]. To avoid incomplete responses and to ensure the comprehensibility of each question, psychologists read and explained the whole interview as clearly as possible [31,48].
Severity of depression was assessed using the Hamilton Rating Scale for Depression (HRS-D), which is designed to rate mood-and depression-related symptomatology by investigating 21 areas. The questionnaire is conceived for adults and rates the severity of depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The patient's score is calculated on the first 17 answers [49].
Anxiety symptoms were investigated using the Hamilton Rating Scale for Anxiety (HAM-A), a clinician-based questionnaire that can be administered as a self-scored survey. It consists of 14 core symptoms and accounts for both psychological and somatic symptoms, comprising anxious mood; tension (including startle response, fatigability, and restlessness); fears (including of the dark/strangers/crowds); insomnia; 'intellectual' (poor memory/difficulty concentrating); depressed mood (including anhedonia); somatic symptoms (including aches and pains, stiffness, and bruxism); sensory (including tinnitus and blurred vision); cardiovascular (including tachycardia and palpitations); respiratory (includ-ing chest tightness and choking); gastrointestinal (including irritable bowel syndrome-type symptoms); genitourinary (including urinary frequency and loss of libido); autonomic (including dry mouth and tension headache) and observed behavior at interview (including restless, fidgety, etc.). Each item is scored from 0 (not present) to 4 (severe); >17/56 is the cut-off to indicate mild anxiety; 25-30 is considered moderate-severe [50].
The Coping Orientation to the Problems Experiences-New Italian Version (COPE-NIV), an improvement of the previous Italian version of the COPE, was administered to investigate coping styles in different contexts. It included five large essentially independent dimensions: social support, avoidance strategies, positive attitude, problem solving, and turning to religion. Altogether, these five dimensions are reliable and stable in time without any essential differences in relation to the level of education, gender, and age. Avoidance strategies were found to be the condition largely associated with emotional distress, whereas positive attitude and problem solving were related to less distress and greater psychological wellbeing. Lastly, social support and turning to religion were not associated with psychological wellbeing. [51].

Statistical Analysis
The descriptive analysis of the sample was reported on demographic (Table 1), clinical, psychometric, and endocrinological variables ( Table 2). In particular, continuous variables were expressed as mean ± standard deviation, while categorical data were expressed through frequencies and percentages. Based on the results of Shapiro normality test and the reduced sample size, we performed a non-parametric analysis. In detail, the Wilcoxon sum rank test was used to compare continuous variables (including age, endocrinological data, and psychometric outcome measures between pre-menopausal and post-menopausal women), and the χ 2 test with continuity correction was used to assess statistical differences in proportions. The semi-structured interview contained multiple-choice questions used to collect data about patients' sexual life before-after the illness, which were codified as ordinal variables at two different times as follows: before the diagnosis of illness (T0) and after the diagnosis of illness (T1). Linear correlations were also computed using Spearman's rho coefficient. Analyses were performed on open-source software R 4.1.3 (R Foundation for Statistical Computer, Vienna, Austria) for Windows. Statistical significance was set at p < 0.05.

Demographic and Clinical Features
A total of 38 female patients with a diagnosis of PD and a mean age of 56.47 ± 10.51 were enrolled in this study. No statistical significance was reported for demographic (Table 1), clinical, and psychometric variables. We distinguished between pre-menopausal (39.50%) with a mean age of 47 ± 6.55 and post-menopausal (60.52%) females with a mean age of 62.6 ± 7.58 PD women. In detail, demographic data showed that most women (65.7%) were married, although two of them did not have children. Then, the quality of satisfaction perceived was lower when it was related to their partners/friends compared to the relationship with parents (both mother and father) and brothers/sisters (see Table 1). From a clinical point of view, we found that PD females presented the following staging of the Hoehn and Yahr scale: 44.7% were in Phase 1; 23.6% were in Phase 1.5; 13% were in Phase 2; 2.63% were in Phase 2.5; 3% were in Phase 3. Moreover, patients were on stable therapy (i.e., without motor fluctuations, on-off phenomena, and dyskinesia): 45% took dopaminergic drugs, 40 % L-Dopa, and 15% both. The endocrinological profile in females (including pre-and post-menopausal) with PD revealed statistical significance concerning testosterone (p < 0.0006), estradiol (p < 0.00), vitamin D3 (p < 0.006), and calcium (0.002). For more detailed information about demographic, clinical, and other variables, see Tables 1  and 2.

Sexual Dysfunction Characteristics
We found statistical differences in sexual intercourse frequency before and after the onset of PD (p < 0.001), while sexual desire does not reach statistical significance (p = 0.15). However, the percentage of women who complained about reduced sexual desire increased after diagnosis (52.7%), specifically in 73.3% of pre-menopausal women and 52.17% of post-menopausal women, rather than before the onset (36.8%) of the illness (see Table 3), with 40% in pre-menopausal women and 39% in post-menopausal females. Nearly half of the PD sample (44%) perceived feelings of anger and frustration during sexual intercourse, and 29.5% of them reported also feelings of fear and anxiety about not satisfying their partner. From our interview, it emerged that 42% of the sample considered themselves less attractive to their partners, and 68.7% of these patients reported reduced sexual desire after the onset of PD. In addition, 55.6% of females perceived changes in their relationship with their partners after the diagnosis of PD. Specifically, 19.04% of them manifested frustration and intolerance for partners; 14.28% of patients felt feelings of embarrassment for their illness; 35.3% showed social isolation, distrust, and difficulty in relating with others; 6.8% of patients reported feeling anger; 10.3% felt more susceptibility; only 14.28% showed more humility and positive feelings. Moreover, patients referred to changes in their sexual intercourse linked to the illness due to motor alteration (10.52%), aging (15.78%), fear of betrayal (26.31%), and reduced intimacy and sexual desire (48.38%).
We also interviewed patients' partners (using two dedicated questions of the same interview) to understand how they were experiencing the behavioral changes of the patients. Interestingly, we found that 71.05% of them reported feeling changes in females' behavior: 48.14% stated that female partners experienced feelings of anger and intolerance (reduced coping strategies) and were more inclined to argue; 22.2% stated that their female partners had avoidant and closed attitudes; 18.51% of females showed depressive symptoms; only 11.15% of females were seen as more compliant and sensitive, according to partners' opinion.
Eventually, we found a linear weak and negative correlation between HRS-A and LH values (rho = −0.30) and a moderate linear positive correlation between avoidance strategies of COPE and HRS-D (rho = 0.38).

Discussion
As far as we know, this is one of the few studies investigating sexuality in female PD patients and the first one focusing on psychological and endocrinological alterations to promote a multimodal approach and to better deal with these disabling problems.
SD is one of the most common, yet under-estimated, non-motor symptoms of PD, and it is often complicated by physical disability, affecting the quality of life of PD patients and their partners [52]. According to the current literature [53], our results showed that SD is highly relevant in female PD patients, especially in pre-menopausal women (<45 years and Hoehn-Yahr stage ≤ 2) [54]. However, SD was also found in 75.8% of older women, with a mean age of 65.1 and a Hoehn-Yahr stage of 2.6 (>10 years of disease) by other authors [55]. Additionally, epidemiological studies have pointed out that loss of libido and decreased sexual desire in PD women have a prevalence of 46.9 to 84% [56]. Another aspect that should be considered is the frequency of difficulties in arousal. In fact, some authors stated that difficulty in arousal or reaching orgasms was present in 87.5% of PD females with a mean age of 61.6 years and 8 years of disease duration. This was in contrast with younger women, who seem to have unaltered arousal and orgasm ability compared to controls [57]. Moreover, it has been found by Buhmann C. et al. [58] that women with PD reported more SD and orgasm-related problems during sexual intercourse, suggesting that partnership problems are more relevant for orgasm dysfunction than physical disorders. According to these findings, we investigated the degree of satisfaction with patients' partners, which was very low compared to the relationship with relatives and friends. The data further suggest that the disease-related SD are not only due to neurobiological changes but also to changes in relationships, given that the diagnosis of a chronic illness affects mood as well as the patient's perspective of his/her life. The mood is strictly related to sexuality in a bidirectional way, and the way one copes with the disease could be fundamental in determining SD [59]. In this vein, we have assessed coping strategies and found that avoidance is potentially correlated with SD. These findings, however, deserve further investigation.
Furthermore, we found that reduced libido was the most prevalent SD, in more than 50% of the sample, whereas in other studies SD prevalence was about 30%. Nevertheless, a recent meta-analysis [60] did not find a higher prevalence of SD in the female PD population compared to healthy controls. This discrepancy could be due to the different assessment tools used, including our specific semi-structured interview built to investigate SD in this specific patient population.
To better understand the etiology of PD-related SD, Varanda S. et al. [61] excluded from their study the psychological causes, although depression and anxiety are much more significant than other variables, as they are known to affect sexuality in the general population as well as in other neurodegenerative disorders [47]. Our multidisciplinary assessment approach (i.e., neurosexological, endocrinological, and psychological) helped us to better demonstrate the potential causes of SD [62]. Indeed, we found that the latter was primarily associated with abnormalities in sex hormone levels. Estrogen loss has been postulated to be associated with female SD in the elderly population since there were significant declines in sexual function by the postmenopausal phase [56]. Okun et al. have shown that a low testosterone level is a recognized cause of depression, fatigue, decreased libido, and decreased work performance [63], as also demonstrated in our study. Then, sex hormones such as estrogen and testosterone may play a crucial role in affecting sexual functioning in females with PD, although research in this area is still scarce [64]. Moreover, we found that in our female sample, there were low levels of Vitamin D3, although we are not able to state if and to which extent the data could be related to SD or associated symptoms. Vitamin D is important for brain development and brain activity, and it has been associated with many neurological diseases, including PD [65]. However, the results of studies investigating the association with non-motor symptoms are conflicting [66,67]. In persons with PD, depression and cognitive impairment seem to be influenced by vitamin D 3 , as reported by Peterson et al. 2013 [68]. Better scores in neuropsychiatric testing, especially verbal fluency and verbal memory, are associated with higher serum levels [69], and vitamin D3 concentration was correlated with depression and anxiety scores [70]. Moreover, SD itself is commonly associated with depression and relationship dissatisfaction, which contributes substantially to sexual unhappiness and reduced quality of life [71,72], as confirmed by our data. Then, an interplay between hormone levels, vitamin D3, and mood alterations should be considered when dealing with SD in female patients with PD. Moreover, coping strategies should also be evaluated in these patients, given that avoidance strategies may further affect sexuality and relationships, as in our sample.
According to the World Health Organization (WHO) (2006) [73], sexual health is a fundamental aspect of life, regardless of the presence of SD, and everyone has the right to conduct their relationships and have personal control over sexual and reproductive behavior with adequate information and treatment. Interestingly, some authors [74] investigated reproductive behavior and pregnancy in PD females. In this context, a pregnancy condition is not a frequent occurrence (since, usually, the disease appears at an older age); however, female patients should be informed of the possible worsening of their non-motor symptoms during pregnancy related to the disease progression of physiological changes and effects of estrogen. Nonetheless, it seems that there is not an increased risk of birth complications or fetal abnormalities in pregnant women with PD, although the assumptions of anti-parkinsonian drugs could complicate childbirth [75].
To sum up, our findings support the idea that sexual disorders in females with PD should be systematically screened and monitored, focusing also on psychological and endocrinological aspects, to reduce the incidence of these non-motor symptoms and for the better management of female patients with PD [76]. In line with some authors [77,78], we believe that early recognition with an adequate and complete treatment of non-motor symptoms of PD, including SD, is essential, owing to multifactorial and multidimensional repercussions on females with PD's quality of life.
Our study has some limitations to knowledge. The sample is relatively small to extend the results to the general female with PD population, and a control group is missing to confer greater methodological rigor. However, data from the literature show a prevalence of loss of libido and decreased sexual desire even in young women with an early onset of PD, suggesting the important role of psychological factors that are more relevant at the onset of SD rather than in men. Nonetheless, in this cross-sectional study, we have investigated the SD-related psycho-endocrinological factors, including mood, anxiety, and coping strategies, beyond the sexual hormone level dosage. This novel approach was aimed to promote the implementation of a more systematic and complete management of these complex non-motor symptoms frequently affecting females with PD.
From a future perspective, it could be interesting if future studies investigate this important issue focusing on the correlations among age, post-menopausal status, stage of PD, motor scores using the UPDRS, and psychological alterations (i.e., depression and anxiety). In fact, we stated that depressive mood can affect female coping strategies, possibly avoiding sexual intercourse. This is why, future and larger studies should perform a multiple regression model to understand the main demographical and clinical features involved in the onset of SD in PD females. Additionally, future research could investigate the presence of SD by examining a matched sample of people of the same age and gender who do not have sexual dysfunction, which could be further helpful in exploring the factors associated with/predicting these disabling symptoms in these patients.

Conclusions
Sexual disorders are the most neglected non-motor symptoms in PD, especially in female patients. Indeed, with this study, we have shown that SD, including loss of libido, is a frequent concern in female subjects with PD, in contrast with the current literature. Given that SD could be associated with mood, behavior, and endocrinological disorders, as well as maladaptive coping strategies, we believe that there is a need for a multidisciplinary approach for a better management of these still overlooked non-motor symptoms. Further larger multicenter studies should be fostered to confirm such a high prevalence of SD in female PD patients and to better establish the role of the different factors in determining these disabling symptoms. Informed Consent Statement: Informed consent was obtained from all subjects/legal guardians involved in this study. Data Availability Statement: Data will be available upon request to the corresponding author.